Spatiotemporal tissue maturation of thalamocortical pathways in the human fetal brain
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eLife assessment
This study presents important new findings regarding prenatal thalamocortical development. The authors present convincing evidence to overcome substantial methodological challenges in charting prenatal brain development in vivo. This work will be of interest to pediatric and developmental neuroscientists and neuroradiologists.
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Abstract
The development of connectivity between the thalamus and maturing cortex is a fundamental process in the second half of human gestation, establishing the neural circuits that are the basis for several important brain functions. In this study, we acquired high-resolution in utero diffusion magnetic resonance imaging (MRI) from 140 fetuses as part of the Developing Human Connectome Project, to examine the emergence of thalamocortical white matter over the second to third trimester. We delineate developing thalamocortical pathways and parcellate the fetal thalamus according to its cortical connectivity using diffusion tractography. We then quantify microstructural tissue components along the tracts in fetal compartments that are critical substrates for white matter maturation, such as the subplate and intermediate zone. We identify patterns of change in the diffusion metrics that reflect critical neurobiological transitions occurring in the second to third trimester, such as the disassembly of radial glial scaffolding and the lamination of the cortical plate. These maturational trajectories of MR signal in transient fetal compartments provide a normative reference to complement histological knowledge, facilitating future studies to establish how developmental disruptions in these regions contribute to pathophysiology.
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eLife assessment
This study presents important new findings regarding prenatal thalamocortical development. The authors present convincing evidence to overcome substantial methodological challenges in charting prenatal brain development in vivo. This work will be of interest to pediatric and developmental neuroscientists and neuroradiologists.
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Reviewer #1 (Public Review):
This study uses a rigorous methodological approach to chart thalamocortical tracts originating from distinct thalamic nuclei, coupled with a model to characterize relative tissue and fluid components along these tracts. This allows a precise description of changes specific to tracts between thalamic nuclei and distinct cortical projection areas. In conjunction with analyses of the microstructure at various distances along the tracts between the thalamus and cortex, these results demonstrate a remarkably consistent organization of thalamic projections as early as 23w, while also highlighting specific gestational-age (GA) dependent processes specific to each tract. This provides a strong step forward in characterizing the development of fetal white matter tracts from non-invasive diffusion MRI data.
Performing …
Reviewer #1 (Public Review):
This study uses a rigorous methodological approach to chart thalamocortical tracts originating from distinct thalamic nuclei, coupled with a model to characterize relative tissue and fluid components along these tracts. This allows a precise description of changes specific to tracts between thalamic nuclei and distinct cortical projection areas. In conjunction with analyses of the microstructure at various distances along the tracts between the thalamus and cortex, these results demonstrate a remarkably consistent organization of thalamic projections as early as 23w, while also highlighting specific gestational-age (GA) dependent processes specific to each tract. This provides a strong step forward in characterizing the development of fetal white matter tracts from non-invasive diffusion MRI data.
Performing detailed neuroimaging analyses of fetal brain development incurs myriad technical challenges, and significant effort has been applied to overcome these. Nevertheless, several aspects of the approaches employed would benefit from better justification. For example, while acquisition parameters necessarily differ from those used in studies in post-natal developmental, or even adult, diffusion MRI studies, this raises several questions regarding the applicability of the modeling analyses employed (in particular, MSMT-CSD with low b-value dMRI data). Additionally, the normalization approach for assessing location-specific differences along each tract is complicated by the gross changes in brain size occurring during this period. Distinguishing the contribution of location-specific changes in microstructure from topographical change (e.g., terminal zones may constitute a smaller relative portion of the tract at later GAs), would enhance the inferences drawn from these results.
It's unclear from the methods how mothers were recruited to get the range of GAs represented, and whether this incurred any demographic correlations to GA. Some more description of recruitment, and a demographic comparison to GA, to clarify that there was not likely to be bias in who was scanned at different times (e.g., 2nd vs 3rd trimester) would strengthen the generalizability of these results.
The statistical basis for comparison among GA groups in the analysis of location-dependent changes in microstructure is not clear. E.g., the characterization of the depths at which GA-dependent differences in tissue fraction occur should be more clearly laid out, such that these observations can be demonstrated quantitatively, rather than reported descriptively.
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Reviewer #2 (Public Review):
Wilson et al. investigated the development of thalamocortical tracts in the fetal brain using in vivo diffusion magnetic resonance imaging (dMRI). In their results, fiber tracts terminating in the prefrontal, superior parietal, and visual cortex connect to discrete areas of the thalamus in an anterior-to-posterior manner. The reported fetal thalamus parcellation is remarkably consistent with parcellation observed in adults, which has significant implications for the development of experience-expectant vs. experience-dependent neurocircuitry. Using along-tract analysis, the authors also identify distinct trajectories of tissue maturation along tracts connecting the thalamus to the medial prefrontal cortex, visual cortex, and superior parietal cortex. Next, these maturation maps were segmented using a …
Reviewer #2 (Public Review):
Wilson et al. investigated the development of thalamocortical tracts in the fetal brain using in vivo diffusion magnetic resonance imaging (dMRI). In their results, fiber tracts terminating in the prefrontal, superior parietal, and visual cortex connect to discrete areas of the thalamus in an anterior-to-posterior manner. The reported fetal thalamus parcellation is remarkably consistent with parcellation observed in adults, which has significant implications for the development of experience-expectant vs. experience-dependent neurocircuitry. Using along-tract analysis, the authors also identify distinct trajectories of tissue maturation along tracts connecting the thalamus to the medial prefrontal cortex, visual cortex, and superior parietal cortex. Next, these maturation maps were segmented using a histologically defined fetal atlas, which revealed unique maturation within fetal neural compartments across gestation. The study introduces an exciting analytical model for bridging the gap between histology and dMRI, enhancing both the interpretability of dMRI metrics in the fetal brain and validating dMRI as a sensitive tool that can reveal organizing principles of fetal brain development. The sample size is impressive for fetal imaging and analyses were completed in individual subject spaces, which helps to minimize the warping of dMRI data.
The conclusions of the paper are largely well-supported by the data, but some aspects of sample composition and data analysis require clarification and extension to ensure the generalizability of the results.
1. Sociodemographic makeup of the sample is insufficiently considered. The authors provide information about fetal gestational age and fetal sex, but no other information about the sample is provided. Readers familiar with the developing human connectome project will know the data was collected in the United Kingdom, but this is not stated explicitly in the manuscript. There is no other information provided about the sample, so it is unclear whether the included 140 maternal-fetal dyads are representative of the broader population. Complex social experiences that vary as a function of income, racial and ethnic identity, and education are potent influences on the developing brain, and there is notable meta-analytic work demonstrating the sociodemographic makeup of a sample alters trajectories of brain development. Brain development in utero has also been shown to vary among fetuses who are later born preterm, yet there is no information about pregnancy complications or delivery (e.g., gestational age at birth) reported in the manuscript. This lack of sociodemographic and health information significantly impedes inference regarding result generalizability.
2. Over half of the collected data were discarded because of failing data quality checks. This is common in fetal data, but it is unclear what thresholds were used to determine exclusion and whether the excluded cases fall evenly along the age spectrum. Typically, MRI data from younger fetuses show greater motion artifacts compared to data collected in older fetuses, which presents a significant confound for the present study that requires careful consideration. It is also unclear whether the motion correction strategies employed in the present study work equally well for all fetal ages. In short, additional analysis and information are required to ensure age-related motion is not unduly impacting the present results.
3. Given that the youngest age group was much smaller than the other groups (n=13), more data is also needed to assess the robustness of the tissue maturation trajectories reported for this young age group.
4. Sensitivity analyses that illustrate the findings are robust to different preprocessing choices would enhance analytic rigor.
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Reviewer #3 (Public Review):
The period that is examined is in the range (21 to 37GW) and uses tractography to delineate five distinct thalamocortical pathways. The paper generates anatomically constrained whole-brain connectomes for each gestational week. The authors parcellate the thalamus according to to streamline connectivity that has been published about two decades ago. The authors delineate the developing thalamocortical pathways and parcellate the fetal thalamus according to its cortical connectivity using diffusion tractography. The study included the primary motor cortex, primary sensory cortex, posterior parietal cortex, dorsolateral prefrontal cortex, and primary visual cortex. With the limitations of the method, the authors delineated five major thalamocortical pathways in each gestational week.
The study finds consistent …
Reviewer #3 (Public Review):
The period that is examined is in the range (21 to 37GW) and uses tractography to delineate five distinct thalamocortical pathways. The paper generates anatomically constrained whole-brain connectomes for each gestational week. The authors parcellate the thalamus according to to streamline connectivity that has been published about two decades ago. The authors delineate the developing thalamocortical pathways and parcellate the fetal thalamus according to its cortical connectivity using diffusion tractography. The study included the primary motor cortex, primary sensory cortex, posterior parietal cortex, dorsolateral prefrontal cortex, and primary visual cortex. With the limitations of the method, the authors delineated five major thalamocortical pathways in each gestational week.
The study finds consistent and distinct origins of different tracts, resembling the adult topology of thalamic nuclei as early as 23W gestation. The study monitors the transient compartment of the subplate and intermediate zone, internal capsule, and establishes references to complement histological knowledge.
The paper's hypothesis is straightforward: "the biological processes occurring in different fetal compartments leads to predictable changes in diffusion metrics along tracts, reflecting the appearance and resolution of these transient zones." Study transient structures, such as subcortical plate or subplate. The authors predict that as subplate neurons disappear the tissue fraction is becoming relatively higher in the deep grey matter and the cortical plate and lower in the subplate. The authors investigate this by characterising the entire trajectory of tissue composition changes between the thalamus and the cortex, to explore the role of transient fetal brain developmental structures on white matter maturational trajectories. The authors demonstrate that along-tract sampling of diffusion metrics can capture temporal and compartmental differences in the second to the third trimester, reflecting the maturing neurobiology of the fetal brain described in histology studies.
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